Analeptically active agents



United States Patent 3,148,113 ANALERTICALLY ACTIVE AGENTS Jan Thesing, Waldstr. Z1, 'ltrautheirn, Germany; Georg Seitz, Martinstr. 10, Darmstadt, Germany; Rudolf Hotovy, Martinstr. 15, Darmstadt, Germany; and Siegmund Sommer, Adelnngstr. 49, Darmstadt, Germany No Drawing. Filed June 5, 1962, Ser. No. 209,069

13 Claims. (Ci. 167--65) isocamphane which carry two methyl groups in position 2 and are substituted on the nitrogen atom by lower alkyl radicals described in German Patent 1,039,061. German Patent 1,001,257 discloses 1,4-endomethylenecyclohexylamines which cause a rise in blood pressure. Furthermore, the blood pressure lowering and ganglion blocking action of methylene substituted 3-amino-norcamphanes was reported in Experientia, vol. 14, page 222 (1958).

The principal object of this invention, therefore, is to provide novel analeptically active compositions which exhibit no deleterious side reactions.

Another object is to provide novel chemical compounds which are beneficially employed as analeptically active agents.

Still another object is to provide a process for effecting analeptic activity in mammals.

Upon further study of the specification and appended claims, still other objects and advantages of the present invention will become apparent.

To attain the objects of the present invention, it has been discovered that certain compounds, on the one hand, are strongly analeptically active, and on the other hand, exhibit no harmful side effects. These analeptical compounds according to this invention are the N-substituted amino-norcamphane derivatives of the following formula:

(GHQ:

i/ in which:

x=1 or 2;

R aryl, aralkyl, cycloalkyl or heterocyclic radicals, which if desired can be substituted one or more times;

R =H, alkyl, cycloalkyl or aryl;

R and R =H, allyl, cycloalkyl or aralkyl radicals which may be the same (except both cannot be H), different or components of a ring which may contain further heteroatoms, each of R through R not containing over 15 carbon atoms as well as their non-toxic acid addition products and their Patented Sept. 8, 1964 of tablets, dragees, capsules, suppositories. solutions, emulsions, etc., for peroral or parenteral administration. Of course, it is also possible and, in some instances, preferable to incorporate in such preparations other beneficial ingredients along with conventional excipients and auxiliary agents.

The preferred dosages of these new compounds are of the same order of magnitude as other conventional analeptical agents such as caffeine and amphetamine. For example, a preferred tablet of this invention is obtained by merely substituting 2 phenyl 3 ethylamino-bicyclo- (2,2,l)-heptane for p-phenylisopropylamine sulfate, mg. for mg., in the following conventional amphetamine tablet:

Mg. fl-Phenylisopropylamine sulfate 5 Lactose 4O Cornstarch 40 Talc 15 thereby obtaining as a preferred embodiment of this invention a tablet of the following composition:

Obviously, the preferred dosages can be varied widely, being dependent on the form of the pharmaceutical preparation and the particular mammal being treated. In general, however, the pharmaceutical compositions preferably contain about 1 to 50 mg. of the analeptical compounds of this invention and about 50 to 500 mg. of a pharmaceutically acceptable vehicular material.

It is important to emphasize that the analeptic agents of this invention represent a significant improvement over the prior art. They cause a mild stimulation of the central nervous system with a noteworthy slight influence upon the blood circulation. The compounds therefore possess a substantial advantage over the usual central nervous system stimulating substances such as caffeine and amphetamine as they also can be administered to patients With high blood pressure. In clinical tests the compounds according to the invention exhibited an increase in spontaneous activity and in the performance level. Indications, above all, are that these compounds will prove useful for hypotonicity, circulation weakness, states of exhaustion, parkinsonism and narcolepsy.

Results of pharmacological trials with compounds according to the invention were published by R. Hotovy et al. in Drug Research, vol. 11, pp. 2024 (1961). Corresponding results of clinical investigations on human beings are reported by D. v. Klebelsberg in Drug Research, vol. 11, pp. 24-27 (1961).

The compounds according to the invention can be prepared from compounds of the formula (C Hz) x in which R R and x have the same significance as above by known alkylation methods whereby hydrogen atoms connected to a nitrogen atom can be substituted and if desired converting the resulting N-mono or N-dialkyl substituted products to the acid addition salts or quaternary ammonium salts. V

For example, compounds of general Formula I can be converted into the N-mono or di-substituted derivatives in a known manner with alkyl or aralkyl halides. In addition, the compounds of Formula I can be condensed with aldehydes to form Schiffs bases and hydrogenating the latter, or heating the latter with an alkylating agent with subsequent hydrolization.

Compounds of Formula II also can be obtained by reacting an amine of Formula I with an aldehyde in the presence of formic acid. In addition, a compound of Formula I can be reacted with an alcohol, preferably a lower aliphatic alcohol, in the presence of Raney nickel. Very good yields of secondary amines of Formula II can be obtained by this reaction. It is furthermore possible to acylate compounds of Formula I by usual methods, such as with acid chlorides or anhydrides and then reduce the CO group in the resulting acyl derivatives to the CH group by usual methods, such as with lithium aluminum hydride.

Acid addition salts of compounds of Formula II can be obtained by treating the latter with an acid which produces physiologically unobjectionable or non-toxic salts. For example, the following salts can be prepared: chloride, orthophosphate, nitrate, sulfate, maleate, fumarate, citrate, ascorbate, tartrate, oxalate, methane sulfonate, sodium disulfonate, hemisuccinate, propionate, butyrate, acetate and the like.

The quaternary ammonium compounds can be produced by reacting compounds of Formula II with any compound suited for quaternization, such as alkyl or aralkyl halides, dialkyl sulfates and the like.

The primary amines of Formula I which serve as starting materials for the production of the novel compounds according to the invention can be prepared in a known manner, for example, by the processes described in I. Am. Chem. Soc., vol. 61, p. 521 (1939), and vol. 73, p. 5068 (1951), and in J. Org. Chem, vol. 8, p. 373 (1943). The reaction occurs by diene addition of omega-nitrostyrene or respectively ring substituted and/ or fl-alkylated nitrostyrene derivatives on cyclopentadiene, dicyclopentadiene or cyclohexadiene with subsequent hydrogenation.

The following table illustrates a number of the compounds according to the invention of the formula pyrrolidino, piperidino and morpholino, wherein R and R are selected from the group consisting of lower alkyl, aralkyl containing 7 to 8 carbon atoms and cyclohexyl.

The following examples will serve to illustrate the preparation of a number of the compounds according to the invention, but are not to be considered as limitative of the remainder of the specification and appended claims.

EXAMPLE 1 Z-Phenyl-3-Methylamino-Bicyclo-(2,2,1)-Heptane 37.46 g. of 2-phenyl-3-amino-bicyclo-(2,2,1)-heptane were heated together with 22 g. of benzaldehyde on a steam bath for 10 minutes. The resulting Schilfs base was freed of the water produced in the reaction under vacuum and then mixed with 20 g. of dimethyl sulfate and heated for 4 hours at 80-85 C. After the reaction mixture cooled it was dissolved in water, acidified with a little hydrochloric acid and the benzaldehyde produced washed out with ether. The washed acid solution was rendered alkaline with sodium hydroxide and the precipitated base was taken up in ether. The ether was evaporated and the residue distilled under vacuum. 28 g. of the base distilled over at 158162 C. at a pressure of 25 mm. Hg.

The hydrochloride of such base produced in ethyl acetate with etheric HCl had a MP. of 198 C. after R4 recrystallization from benzene-petroleum-ether. 3 l EXAMPLE 2 1 (CH2) Z-Phenyl-S-Ethylamlno-Bzcyclo- (2,2,1 -Hepztarte R1 (a) 28.05 g. of 2-phenyl-3-armno-b1cyclo-(2,2,1)-hepwhich have been produced: tane were mixed with 6.9 g. of acetaldehyde while cool M.P. Hydrochlor- No R1 R R3 R4 X ide (a), 13.1. Base H H 1 a=l98 H CH3 1 =245 H CH 1 a=l40.

H H 1 a=192 H 0211 1 a=222. H CH3 1 a=200. H H l a=206. H CH3 1 b=138 (2 mum). H H Cyclohen 1 b= (0.05 mm.). H CH CyclohexyL- 1 b= (0.1 111131.). E H 11-CaH7 l a=l84. H H 1 21:185. H can 1 a=175. H CH3 1 a=268. H CH3 1 a=258. H CH3 1 a=222. H CH3 1 a=265. H OH; 1 a=284. H CH3 1 a=257. H CH3 1 a=256 H CH3 1 3 246 H CH3 1 a=242. CH3 CH 1 b=113 (0.4 mm.) H H 2 a=272. CGH5 H CH3 2 3 269. k-Naphthyl H CH3 1 a=307. 27 B-Pyridyl H CH3 1 a=243.

RH- t 28 Calls" H pyrrolidino 1 21:216. 29 C H5 H piperidino 1 a=222. 30 OGH H morpholino 1 a=258.

1 Those two compounds dificr from one another by an additional methyl group as compound 3 is the quaternary ammonium compound of compound 2 (of. Example 13).

ing. The mixture was then heated under reflux on a steam bath for 20 minutes and then freed from the water produced in the reaction at 60 C. under vacuum. The crude base was dissolved in 300 cc. of methanol and hydrogenated with 2 g. of prereduced platinum oxide. After the calculated quantity of hydrogen had been taken up, the solvent was distilled off under vacuum and the residue taken up in dilute HCl and the neutral byproducts shaken out with ether. The aqueous solution was rendered alkaline with sodium hydroxide and then extracted with ether. 13.2 g. of the base of a boiling point of 128131 C. at 0.1 mm. Hg were recovered from the ether solution. The hydrochloride thereof had a melting point of 192 C. after recrystallization from acetone.

(b) 25 g. of 2-phenyl-3-amino-bicyclo-(2,2,1)-hep tane were boiled together with g. of Raney nickel and 75 cc. of absolute alcohol under reflux for 15 hours. The catalyst was filtered 01f and the filtrate neutralized with dilute HCl and then evaporated to dryness under vacuum. The hydrochloride which remained as the residue was purified by recrystallization from acetone or dioxane-petroleum ether. The yield was 2.5 g. having a M.P. of 192 C.

EXAMPLE 3 2- henyl-3-Diethylamino-Bicyclo- (2,2,1 -Heptane 3.8 g. of the 2-phenyl-3-ethylamino-bicyclo-(2,2,1)- heptane hydrochloride produced according to Example 2 were mixed with cc. of pyridine and 3.8 g. of acetic anhydride and the mixture permitted to stand at room temperature for 12 hours. The solution which had become clear during standing was completely distilled off under vacuum. The residue was triturated with water, and the insoluble portion taken up in ether and the ether solution washed with dilute HCl, bicarbonate solution and water. A residue of 2.6 g. of the crystallized crude acetyl compound was obtained after evaporation of the ether. It was dissolved in 20 cc. of absolute ether and then a slight excess of lithium alanate in cc. of absolute ether added thereto. The mixture was stirred for 2 hours at room temperature and then boiled under reflux for a few minutes. Then 5 g. of tartaric acid in 50 cc. of water were carefully added and the mixture rendered strongly alkaline with sodium hydroxide.

The ether layer was separated off and the ether evaporated to leave the sought base. It Was dissolved in ethyl acetate and etheric HCl added thereto. 2.6 g. of hydrochloride salt were produced which melted at 222 C. after recrystallization from acetone.

EXAMPLE 4 2-Cyclohexyl-3-Dimethylamino-Bicyclo-(2,2,1)- Heptane 21.5 g. of 2-phenyl-3-dimethylamino-bicyclo-(2,2,1)- heptane in 600 cc. of methanol containing 50 g. of Raneynickel were hydrogenated at 185 C. under a gauge pressure of about 200 atmospheres. The catalyst was filtered off and the filtrate evaporated to dryness under vacuum. The residue was rendered strongly alkaline and then extracted with methylene chloride. The residue remaining after evaporating the methylene chloride was dissolved in absolute alcohol and acidified with etheric HCl. 12.9 g. of the hydrochloride were obtained which melted at 245 C. after recrystallization.

EXAMPLE 5 2-Plzenyl-3-Cyclohexylamino-Bicyclo-(2,2,1 -Heptane 18.7 g. of 2-phenyl-3-amino-bicyclo-(2,2,1)-heptane were heated together With 10 g. of cyclohexanone for 20 hours at 100 C. After cooling, the crude Schiffs base was dissolved in 180 cc. of methanol and the solution hydrogenated at a gauge pressure of 3 atmospheres after the addition of 2 g. of prereduced platinum oxide. The hydrogen taken up ceased after 30 minutes. The catalyst was filtered off and the filtrate concentrated and then distilled under vacuum. 18.2 g. of the base with a boiling point of C. at 0.05 mm. Hg were ob,-

tained.

EXAMPLE 6 2-Ph enyl-3-Cycl0hexylm ethylamino-Bicyclo- (2,2,1 Heptane EXAMPLE 7 2 Phenyl 3-Ethylpr0pylamino-Bicyclo-(2,2,1)-Heptane 43.07 g. of the 2-phenyl-3-ethylamino-bicyclo-(2,2,1)- heptane obtained according to Example 2 were heated together with 12.3 g. of n-propyl bromide for 12 hours at 120 C. in a bomb tube. After cooling the reaction miX ture was diluted with absolute ether, and the solids separated off and the ether solution of the reaction product shaken with a little acetic anhydride and sufficient soda that the mixture remained alkaline. The desired base was recovered from the ether solution by evaporation of the ether. It had a boiling point of 138 C. at 1 mm. Hg. The hydrochloride salt melts at C EXAMPLE 8 2-(3,4-Dihydr0xyphenyl)-3-Dimethylamin0-Bicyclo- (2,2,1 )-Heptane chloride salt having a melting point of 255 C. were obtained.

EXAMPLE 9 2-Phenyl-3-Methyl-3-Dimethylamino-Bicyclo-(2,2,1 Heptane 7.6 g. of 2 phenyl-3-methyl-3-amino-bicyclo-(2,2,1)- heptane, 6.9 g. of formic acid and 7.5 g. of 30% formaldehyde solution were heated to 100 C. for 10 hours. The reaction solution was cooled and alkalized and extracted with ether. 7 g. of the base having a boiling point of 113 C. at 0.4 mm. Hg were recovered from the washed and dried ether extract.

EXAMPLE 10 2 Phenyl 3-Dimethylamina-Bicycle-(2,2,2)-Octane 7.75 g. of 2-phenyl-3-amino-bicyclo-(2,2,2)-octane-hydrochloride, 4.42 g. of sodium formate, 3.15 cc. of formic acid and 69 g. of 30% formaldehyde solution were heated together for 10 hours at 100 C. As in Example 9 the reaction mixture was cooled, alkalized and extracted with ether and the base recovered from the ether extract. 7.2 g. of the hydrochloride salt were obtained from the crude base. Such hydrochloride after recrystallization from alcohol-ether had a melting point of 260 C 7 EXAMPLE 11 2 (m-Naphrhyl) 3 Dimethylamino Bicycle-(2,2,1)-

Heptane The free base was produced from 5.5 g. 2-(a-naphthyl)- 3-amino-bicyc1o-(2,2,1)-heptane-hydrochloride by alkalizing, shaking out with methylene chloride and distilling 011 the solvent. The free base was mixed with 16.4 g. of 35% formaldehyde solution and 4.6 g. of formic acid and heated for 3 hours at 120 C. The reaction mixture was processed as in Example 9. 3.8 g. of the hydrochloride salt having a melting point of 307 C. were obtained.

EXAMPLE l2 2-Phenyl-3-Trimethylammonium-Bicyclo-(2,2,1)-Heptane 7.4 g. of Z-(B-pyridyl)-3-amino-bicyclo-(2,2,1)-heptane were heated together with 7.9 g. of formic acid, 1 cc. of water and 8.7 g. of 30% formaldehyde solution for 12 hours at 100 C. 39.5 cc. of n-HCl were added to the reaction mixture and it was then evaporated to dryness under vacuum. The residue was recrystallized from alcohol-ether. The dihydrochloride thus obtained has a melting point of 243 C.

EXAMPLE 13 2-Plzeny[-3-Trimethylammonium-Bicycl0-(2,2,1)-Heptune-Chloride 6.45 g. of 2-phenyl-3-dimethylamino-bicyclo-(2,2,1)- heptane were mixed with 15 cc. of absolute alcohol and 5.1 g. of methyl iodide. The methoiodide started precipitating out after a short time. The precipitation was completed after several hours by the addition of absolute ether. The very hygroscopic salt was recrystallized from isopropyl alcohol. The methoiodide was converted to the methochloride by shaking with silver chloride in dilute alcohol or by distilling off with methanolic HCl. The methochloride after recrystallization from acetone had a melting point of 140 C.

EXAMPLE 14 2 Phenyl 3-Pyrr0lidino-Bicyclo-(2,2,1)-Heptane 9.35 g. of 2-phenyl-3-amino-bicyclo- (2,2,1)-heptane together with 11.8 g. of tetramethy'lene bromide and 50 g. of aqueous sodium hydroxide were heated for 10 hours under reflux with stirring. The oily base after cooling was extracted with ether and the hydrochloride extracted with dilute HCl from the ether extract. The HCl extract was alkalized and the precipitated base extracted with ether and the ether extract dried with sodium sulfate. The ether was evaporated 011 the dried extract and the residue dissolved in acetone, neutralized with etheric HCl. After addition of further ether, 12.3 g. of crude 2-phenyl- 3-pyrrolidino-bicyclo-(2,2,1)-heptane-hydrochloride of a melting point of 207 C. were obtained. After recrystallization from acetone or dioxane its melting point rose to 216 C.

EXAMPLE 15 2 Phenyl 3-Piperz'din0-Bicycl0-(2,2,1)-Heptane In a manner analogous to Example 14 2-phenyl-3-piperidino-bicyclo- (2,2,1 -heptane-hydrochloride was obtained from 9.35 g. 2-phenyl-3-amino-bicyclo-(2,2,1)-heptane and 12.65 g. of pentamethylene bromide. After recrystallization from acetone it had a melting point of 222 C.

(2,2,1)-heptane and 7.9 g. of {3,,B'-dichlorodiethylether. It had a melting point of 258 C.

EXAMPLE 17 Z-(Para-Fluoroplzenyl -3-Dimethy[amino-Bicycle- (2,2,1)-Heptane In a manner analogous to Example 8 7 g. of 2-(parafluorophenyl) 3-dimethylamino-bicyclo-(2,2,1)-heptane were obtained from 10 g. 2-(p-fiuorophenyl) 3 aminobicyclo-(2,2,1)-heptane hydrochloride. The obtained hydrochloride melts at 222 C.

EXAMPLE 18 2-Pheny[-3-Benzylamino-Bicyclo-(2,2,1 )-Heptane 74.8 g. of 2-phenyl-3-amino-bicyclo (2,2,1) heptane are heated with 26.6 g. of benzyl chloride for 8 hours to The cooled reaction product is extracted with ether. The ethereal layer is separated from the residue, washed with water, dried and neutralized with ethereal hydrogen chloride. The precipitated hydrochloride is crystallized by treating it with acetone. Melting point 184 C.

EXAMPLE l9 2-Phenyl-3-(N-B-Phenylethyl-N-Ethyl -A mino- Bicycl0-(2,2,1)-Heptane In an analogous manner to Example 18, 2-phenyl-3 (N-B-phenylethyl N ethyl) amino bicyclo (2,2,1)- heptane is obtained from 21.5 g. of 2-phenyl-3-ethylaminobicyclo-(2,2,1)-heptane and 9.25 g. of phenylethyl bromide. The base crystallizes from methanol and has a melting point of 61 C.

In CNS-screening tests, the compounds of this invention were administered to mice to determine their effectiveness in increasing the locomotoric activity and the minimum dose required to provide a discernible stimulation. The following table presents typical results of these tests with some examples of the analeptical compounds embraced by this invention.

TABLE CNS -screening minimum dosage Substance: mg. kg -oral 2-phenyl-3-dimethylamino-bicyclo- (2,2,l)-heptane l0 2-phenyl-3 -ethylamino-bicyclo- (2,2,l)-heptane 3 2-phenyl-3-methylethylamino-bicyclo- (2,2,1 -heptane 5 2-phenyl-3 -propylamino-bicyclo- (2,2,1)-heptane 5 2-phenyl-3-diethylamino-bicyclo- (2,2,1)-heptane l-3 2-phenyl-3-isopropylamino-bicyclo- (2,2,1)-heptane 5-10 2-phenyl-3 -pyrrolidino-bicyclo- (2,2,1 )-heptane 5 Z-p-fiuorophenyl-3-dimethylamino-bicyc1o- (2,2,1 )-heptane 5 A description of the CNS-screening test can be found in Archives Internationales de Pharmacodynamic et cle Thrapie, vol. 118, p. 358 (1959); Pfiiigers Archiv PhysioL. vol. 254, p. 262 (1951) and Drug Research, vol. 11, pp. 20-24 (1961).

Of the tabulated compounds it is of interest to note that the first compound, Z-phenyl-3-dimethylamino-bicyclo-(2,2,1)-heptane is mentioned in an article by Parham et al., Journal of American Chemical Society, vol. 73, page 5070, column 2. It is also apparent, however, that the mention of this compound was merely incidental to an investigation of reactions of 2-phenyl-3-nitrobicyclo- (2,2,1)-heptene-5, and that there is absolutely no mention or suggestion of any contemplated field of use for any of the compounds described in the article. Consequently, it is both surprising and unexpected that this compound can eifect analeptic activity in mammals without any deleterious side reactions.

It is furthermore of interest to note that the other tabulated compounds are, in contrast, completely novel creased activity over the known 2-phenyl-3 -dimethylamino-bicyclo-(2,2,1)-heptane. For example, 2-p-fluorophenyl-3-dimethylamino-bicyclo (2,2,1) heptane is two times more active, and both 2-phenyl-3-ethylamino-bicy- 'clo-(2,2,1)-heptane and 2-phenyl-3-diethylamino-bicyclo- (2,2,1)-heptane are three times more active than the known compound.

Thus, the novel compounds of this invention which exhibit an unexpected superiority over the incidental disclosure of 2-phenyl 3 dimethylamino bicycle-(2,2,1)- heptane, are represented by the following formula:

in which R =aryl, aralkyl, cycloalkyl or heterocyclic radicals, which if desired can be substituted one or more times;

R =H, alkyl, cycloalkyl or aryl;

R and R =H, alkyl, cycloalkyl or aralkyl radicals which may be the same (except both cannot be H), different or components of a ring which may contain further heteroatoms, each of R through R; not containing over 15 carbon atoms and R and R not being methyl at the same time when R =phenyl, R =H and x: 1,

as well as their non-toxic acid addition products and their quaternary ammonium compounds.

This application is a continuation-in-part of copending application Serial No. 44,879, filed July 25, 1960, now abandoned.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Consequently, such changes and modifications are properly, equitably and intended to be within the full range of equivalence of the following claims.

What is claimed is:

1. A process for effecting analeptical activity in mammals, without, at the same time, causing any deleterious effects on the circulatory system, which process comprises administering to said mammals a therapeutic dosage formulation comprising at least one mg. of at least one member selected from the group consisting of a compound of the formula:

in which x is an integer from 1 to 2, R is a member of the group consisting of phenyl, naphthyl, cyclohexyl, pyridyl and phenyl substituted by member selected from the group consisting of halogen, hydroxy, lower alkyl and lower alkoxy substituents, R is a radical selected from the group consisting of hydrogen and lower alkyl, and Y is selected from the group consisting of pyrrolidino, piperidino and morpholino, wherein R and R are selected from the group consisting of lower alkyl, aralkyl containing 7 to 8 carbon atoms, cyclohexyl; and pharmaceutically acceptable acid addition salts thereof.

2. A process for effecting analeptical activity in mammals, without, at the same time, causing any deleterious effects on the circulatory system, which process comprises administering to said mammals a therapeutical dosage for- 1Q mulation comprising at least one mg. of 2-phenyl-3-di ethylamino-bicyclo- (2,2, 1 -heptan e.

3. A process for effecting analeptical activity in mammals, without, at the same time, causing any deleterious effects on the circulatory system, which process comprises administering to said mammals a therapeutic dosage formulation comprising at least one mg. of 2-phenyl-3- methylethylamino-bicyclo-(2,2,1 -heptane.

4. A process for effecting analeptical activity in mam- 'mals, without, at the same time, causing any deleterious effects on the circulatory system, which process comprises administering to said mammals a therapeutic dosage formulation comprising at least one mg. of 2-phenyl-3- pyrrolidino-bicyclo-(2,2,1 )-heptane.

5. A process for effecting analeptical activity in mammals, without, at the same time, causing any deleterious effect on the circulatory system, which process comprises administering to said mammals a therapeutic dosage formulation comprising at least one mg. of 2-p-fiuorophenyl-3 -dimethylamino-bicyclo-( 2,2,1 -heptane.

6. A process for effecting analeptical activity in mammals, without, at the same time, causing any deleterious effects on the circulatory system, which process comprises administering to said mammals a therapeutic dosage formulation comprising at least one mg. of 2-phenyl-3-monoethylamino-bicyclo- 2,2,1 )-heptane.

7. A therapeutic dosage formulation comprising about 1-50 mg. of at least one member of the group consisting of a compound of the formula:

pyrrolidino, piperidino and morpholino, wherein R and R are selected from the group consisting of lower alkyl, aralkyl containing 7 to- 8 carbon atoms, cyclohexyl; and pharmaceutically acceptable addition salts thereof, as an essential analeptic agent incorporated into pharmaceutically acceptable vehicular excipients; whereby said formulation produces an analeptic activity without, at the same time, causing any deleterious effects on the circulatory system upon administration to mammals.

8. A therapeutic dosage formulation comprising at least about one mg. of 2-phenyl-3-diethylamino-bicyclo- (2,2,1)-heptane as an essential analeptic agent incorporated into pharmaceutically acceptable vehicular excipients; whereby said formulation produces an analeptic activity without, at the same time, causing any deleterious effects on the circulatory system upon administration to mammals.

9. A therapeutic dosage formulation comprising at least about one mg. of 2-phenyl-3-methylethylamino-bicyclo-(2,2,1)-heptane as an essential analeptic agent incorporated into pharmaceutically acceptable vehicular excipients; whereby said formulation produces an analeptic activity without, at the same time, causing any deleterious effects on the circulatory system upon administration to mammals.

10. A therapeutic dosage formulation comprising at least about one mg. of 2-phenyl-3-pyrrolidino-bicyclo- (2,2,1)-heptane as an essential analeptic agent incorporated into pharmaceutically acceptable vehicular excipients; whereby said formulation produces an analeptic 3,1as,11s

11 activity without, at the same time, causing any deleterious effects on the circulatory system upon administration to mammals.

11. A therapeutic dosage formulation comprising at least about one mg. of 2-p-fluorophenyl-3-dimethylaminobicyclo-(2,2,1)-heptane, as an essential analeptic agent incorporated into pharmaceutically acceptable vehicular excipients; whereby said formulation products an analeptic activity without, at the same time, causing any deleterious effects on the circulatory system upon administration to mammals.

12. A therapeutic dosage formulation comprising at least about one mg. of 2-phenyl-3-monoethylamino-bicyclo-(2,2,l)-heptane as an essential analeptic agent incorporated into pharmaceutically acceptable vehicular excipients; whereby said formulation produces an analeptic activity Without, at the same time, causing any deleterious effects on the circulatory system upon administration to mammals.

13. The formulation of claim 12, wherein the 2-phenyl- 3-moncethylamino-bicyclo-(2,2,1)-heptane is present in a 0 dosage of about 150 mg.

No references cited. 

1. A PROCESS FOR EFFECTING ANALEPTICAL ACTIVITY IN MAMMALS, WITHOUT, AT THE SAME TIME, CAUSING ANY DELETERIOUS EFFECTS ON THE CIRCULATORY SYSTEM, WHICH PROCESS COMPRISES ADMINISTERING TO SAID MAMMALS A THERAPEUTIC DOSAGE FORMULATION COMPRISING AT LEAST ONE MG. OF AT LEAST ONE MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 